Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens

Wesseling, Charlotte M J; Slingerland, Cornelis J.; Veraar, Shanice; Lok, Samantha; Martin, Nathaniel I.

doi:10.1021/acsinfecdis.1c00466

Cited by 15 publications

(23 citation statements)

References 63 publications

(206 reference statements)

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“…Interestingly, our studies also revealed benchmark bis-amidine 9 to be hemolytic. These findings further highlight the importance of assessing OM selectivity when pursuing synergists …”

Section: Non-steroid Small-molecule Synergistsmentioning

confidence: 79%

“…These findings further highlight the importance of assessing OM selectivity when pursuing synergists. 241 …”

Section: Non-steroid Small-molecule Synergistsmentioning

confidence: 99%

“…Inspired by these findings, our group recently undertook a broad SAR investigation wherein a number of structurally unique bis-amidines were synthesized and evaluated as synergists . Specifically, we focused our attention on the length and rigidity of the linker motif as well as the geometry of the amidine groups on the aromatic rings.…”

Section: Non-steroid Small-molecule Synergistsmentioning

confidence: 99%

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Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Wesseling

Martin

2022

ACS Infect. Dis.

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New approaches to target antibacterial agents toward Gram-negative bacteria are key, given the rise of antibiotic resistance. Since the discovery of polymyxin B nonapeptide as a potent Gram-negative outer membrane (OM)-permeabilizing synergist in the early 1980s, a vast amount of literature on such synergists has been published. This Review addresses a range of peptide-based and small organic compounds that disrupt the OM to elicit a synergistic effect with antibiotics that are otherwise inactive toward Gram-negative bacteria, with synergy defined as a fractional inhibitory concentration index (FICI) of <0.5. Another requirement for the inclusion of the synergists here covered is their potentiation of a specific set of clinically used antibiotics: erythromycin, rifampicin, novobiocin, or vancomycin. In addition, we have focused on those synergists with reported activity against Gram-negative members of the ESKAPE family of pathogens namely, Escherichia coli , Pseudomonas aeruginosa , Klebsiella pneumoniae , and/or Acinetobacter baumannii . In cases where the FICI values were not directly reported in the primary literature but could be calculated from the published data, we have done so, allowing for more direct comparison of potency with other synergists. We also address the hemolytic activity of the various OM-disrupting synergists reported in the literature, an effect that is often downplayed but is of key importance in assessing the selectivity of such compounds for Gram-negative bacteria.

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“…Interestingly, our studies also revealed benchmark bis-amidine 9 to be hemolytic. These findings further highlight the importance of assessing OM selectivity when pursuing synergists …”

Section: Non-steroid Small-molecule Synergistsmentioning

confidence: 79%

“…These findings further highlight the importance of assessing OM selectivity when pursuing synergists. 241 …”

Section: Non-steroid Small-molecule Synergistsmentioning

confidence: 99%

Section: Non-steroid Small-molecule Synergistsmentioning

confidence: 99%

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Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Wesseling

Martin

2022

ACS Infect. Dis.

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“…Compounds that physically disrupt the integrity of the OM ( e.g. , polymyxins, pentamidine, peptide S25) can be used as adjuvants to sensitize Gram-negative bacteria to otherwise-inactive antimicrobials. ,− SPR741 (NAB741) is a polymyxin analogue that has reduced antimicrobial potency and renal toxicity but retains its ability to disrupt the OM and is able to potentiate a range of antibiotics against Gram-negative bacteria. ,, Here we found that SPR741 was also successful in potentiating metergoline and analogues 15 , 28 , 38 , and 44 against Gram-negative bacteria (Table ). For example, in the presence of 10 μg/mL SPR741, the MICs for 3-CF 3 derivative 28 were reduced >128-, >64-, >32-, and >128-fold against WT E.…”

Section: Resultsmentioning

confidence: 74%

Antibacterial Activity of Metergoline Analogues: Revisiting the Ergot Alkaloid Scaffold for Antibiotic Discovery

Johnson

Ellis

Piquette

et al. 2022

ACS Med. Chem. Lett.

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Metergoline is a semisynthetic ergot alkaloid identified recently as an inhibitor of the Gram-negative intracellular pathogen Salmonella Typhimurium (S. Tm). With the previously unknown antibacterial activity of metergoline, we explored structure–activity relationships (SARs) with a series of carbamate, urea, sulfonamide, amine, and amide analogues. Cinnamide and arylacrylamide derivatives show improved potency relative to metergoline against Gram-positive bacteria, and pyridine derivative 38 is also effective against methicillin-resistant Staphylococcus aureus (MRSA) in a murine skin infection model. Arylacrylamide analogues of metergoline show modest activity against wild-type (WT) Gram-negative bacteria but are more active against strains of efflux-deficient S. Tm and hyperpermeable Escherichia coli. The potencies against WT strains of E. coli, Acinetobacter baumannii, and Burkholderia cenocepacia are also improved considerably (up to >128-fold) with the outer-membrane permeabilizer SPR741, suggesting that the ergot scaffold represents a new lead for the development of new antibiotics.

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“…Pentamidine disrupts bacterial OM by binding to lipopolysaccharide (LPS). Subsequently, efforts have been made to probe the structure and activity relationships by modifying the linker between the two amidine groups . Along this line, several other small-molecule bacterial sensitizers with diverse mechanisms such as LPS binding, OM protein biogenesis impairment, and efflux inhibition have been discovered. ,− Such compounds serve as excellent examples of initial success, with much room for exploring improved potency, mechanistic understanding, establishing in vivo activity, and examining broad chemical space for success.…”

Section: Introductionmentioning

confidence: 99%

Restoring and Enhancing the Potency of Existing Antibiotics against Drug-Resistant Gram-Negative Bacteria through the Development of Potent Small-Molecule Adjuvants

Choudhury

Yang

et al. 2022

ACS Infect. Dis.

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The rapid and persistent emergence of drug-resistant bacteria poses a looming public health crisis. The possible task of developing new sets of antibiotics to replenish the existing ones is daunting to say the least. Searching for adjuvants that restore or even enhance the potency of existing antibiotics against drug-resistant strains of bacteria represents a practical and cost-effective approach. Herein, we describe the discovery of potent adjuvants that extend the antimicrobial spectrum of existing antibiotics and restore their effectiveness toward drug-resistant strains including mcr-1-expressing strains. From a library of cationic compounds, MD-100, which has a diamidine core structure, was identified as a potent antibiotic adjuvant against Gram-negative bacteria. Further optimization efforts including the synthesis of ∼20 compounds through medicinal chemistry work led to the discovery of a much more potent compound MD-124. MD-124 was shown to sensitize various Gram-negative bacterial species and strains, including multidrug resistant pathogens, toward existing antibiotics with diverse mechanisms of action. We further demonstrated the efficacy of MD-124 in an ex vivo skin infection model and in an in vivo murine systemic infection model using both wild-type and drug-resistant Escherichia coli strains. MD-124 functions through selective permeabilization of the outer membrane of Gram-negative bacteria. Importantly, bacteria exhibited low-resistance frequency toward MD-124. In-depth computational investigations of MD-124 binding to the bacterial outer membrane using equilibrium and steered molecular dynamics simulations revealed key structural features for favorable interactions. The very potent nature of such adjuvants distinguishes them as very useful leads for future drug development in combating bacterial drug resistance.

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Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens

Cited by 15 publications

References 63 publications

Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Antibacterial Activity of Metergoline Analogues: Revisiting the Ergot Alkaloid Scaffold for Antibiotic Discovery

Restoring and Enhancing the Potency of Existing Antibiotics against Drug-Resistant Gram-Negative Bacteria through the Development of Potent Small-Molecule Adjuvants

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